Lauriane Goldwirt1,2, Kevin Beccaria3, Alain Ple4, Hélène Sauvageon4, Samia Mourah4,5. 1. Pharmacology Department, Saint-Louis Hospital, AP-HP, 1 Avenue Claude Vellefaux, 75010, Paris, France. lauriane.goldwirt@aphp.fr. 2. INSERM UMR_S976, Université Paris-Diderot, Sorbonne Paris Cité, Paris, France. lauriane.goldwirt@aphp.fr. 3. Department of Pediatric Neurosurgery, Necker Hospital, AP-HP, Université Paris Descartes, Sorbonne Paris Cité, 75015, Paris, France. 4. Pharmacology Department, Saint-Louis Hospital, AP-HP, 1 Avenue Claude Vellefaux, 75010, Paris, France. 5. INSERM UMR_S976, Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.
Abstract
PURPOSE: Central nervous system (CNS) dissemination occurs in 4.1% of mantle cell lymphoma (MCL) patients and clinically significant CNS involvement in chronic lymphocytic leukemia (CLL) patients reaches 4%. Ibrutinib, an orally administered Bruton's tyrosine kinase (BTK) inhibitor, has shown substantial activity in CLL or MCL patients with CNS localization, and in primary central nervous system lymphoma (PCNSL). The drug efficacy to treat primary or secondary CNS impairments relies on its brain distribution through the blood-brain barrier (BBB), the aim of the present work was to study the brain distribution of ibrutinib using an in vivo mice model. METHODS: Brain and plasma pharmacokinetics of ibrutinib were assessed in a healthy Swiss mice model. Brain accumulation of ibrutinib was evaluated through an escalation single-dose study and a multiple-dose study in whole brain and in its specific anatomic structures. Ibrutinib plasma and brain quantification was performed using a validated liquid-chromatography mass tandem spectrometry method. RESULTS: Maximal concentration of ibrutinib in plasma and brain were close thus showing that ibrutinib rapidly crosses the BBB in 0.29 h (0.2-0.32 h) [median (min-max)]. Ibrutinib brain exposure was also correlated to the dose, and correlated to plasma exposure. AUC0-t brain to AUC0-t plasma ratio average for ibrutinib was found to reach 0.7 and ibrutinib accumulates in the ventricle area. CONCLUSION: The high level of ibrutinib brain distribution supports the clinical efficacy of this drug in CNS localization of MCL, CLL or PCNSL.
PURPOSE: Central nervous system (CNS) dissemination occurs in 4.1% of mantle cell lymphoma (MCL) patients and clinically significant CNS involvement in chronic lymphocytic leukemia (CLL) patients reaches 4%. Ibrutinib, an orally administered Bruton's tyrosine kinase (BTK) inhibitor, has shown substantial activity in CLL or MCLpatients with CNS localization, and in primary central nervous system lymphoma (PCNSL). The drug efficacy to treat primary or secondary CNS impairments relies on its brain distribution through the blood-brain barrier (BBB), the aim of the present work was to study the brain distribution of ibrutinib using an in vivo mice model. METHODS: Brain and plasma pharmacokinetics of ibrutinib were assessed in a healthy Swiss mice model. Brain accumulation of ibrutinib was evaluated through an escalation single-dose study and a multiple-dose study in whole brain and in its specific anatomic structures. Ibrutinib plasma and brain quantification was performed using a validated liquid-chromatography mass tandem spectrometry method. RESULTS: Maximal concentration of ibrutinib in plasma and brain were close thus showing that ibrutinib rapidly crosses the BBB in 0.29 h (0.2-0.32 h) [median (min-max)]. Ibrutinib brain exposure was also correlated to the dose, and correlated to plasma exposure. AUC0-t brain to AUC0-t plasma ratio average for ibrutinib was found to reach 0.7 and ibrutinib accumulates in the ventricle area. CONCLUSION: The high level of ibrutinib brain distribution supports the clinical efficacy of this drug in CNS localization of MCL, CLL or PCNSL.
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